rs1553939600

Positions:

• chr2-151631295-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001164507.2(NEB):​c.9465del​(p.Ile3156LeufsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P3155P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -0.311

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-151631295-TG-T is Pathogenic according to our data. Variant chr2-151631295-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151631295-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9465del	p.Ile3156LeufsTer16	frameshift_variant	66/182	ENST00000427231.7
NEB	NM_001164508.2	c.9465del	p.Ile3156LeufsTer16	frameshift_variant	66/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9465del	p.Ile3156LeufsTer16	frameshift_variant	66/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9465del	p.Ile3156LeufsTer16	frameshift_variant	66/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8854-118del		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000198 AC: 29 AN: 1461566 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nemaline myopathy (MIM#256030). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0219 - This variant is non-coding in an alternative transcript. However, many pathogenic variants in the same coding exon have been reported (ClinVar, UCSC). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (PMID: 32222963, ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic (ClinVar), and in a compound heterozygous patient with severe nemaline myopathy (PMID: 25205138). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (p.Arg8094Serfs*9) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (19G000860). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 07, 2020	PVS1, PM2, PS4_supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2021	ClinVar contains an entry for this variant (Variation ID: 550322). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile3156Leufs*16) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). -

Nemaline myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 11, 2022

Variant summary: NEB c.9465delC (p.Ile3156LeufsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248870 control chromosomes (gnomAD). c.9465delC has been reported in the literature in an individual affected with Nemaline Myopathy (Lehtokari_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2022

Identified in the presence of a second NEB variant, phase unknown, in a patient with a form of NEB-related nemaline myopathy characterized by pronounced weakness of axial muscles with relative sparing of limb muscles in the published literature (Lehtokari et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205138) -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553939600; hg19: chr2-152487809;